A large number of industries are interested in the production of micron and submicron particles for different applications. The need for an apparatus and a method to produce submicron particles is particularly pronounced in the pharmaceutical field.
There are several reasons for employing drugs as fine powders in pharmaceutics, such as the need to improve the bioavailability or the requirements for specific pharmaceutical forms (nasal, ophthalmic, injectables, modified release), etc.
The conventional techniques for particle size reduction (grinding, milling, spray drying, freeze drying) present many disadvantages, in particular for biological active principles. For instance during the initial step of freeze drying, the drug (protein) and the buffer and other ingredients tend to concentrate leading to changes in pH and ionic strength; this can cause protein denaturation. Concerning spray drying, the main limitations of this technique are essentially high costs, thermal degradation and low efficiency with low yield and high levels of residual moisture.
Within the last decade, different processes have been proposed for micron and submicron particles formation by utilizing supercritical fluid techniques (RESS, GAS, SEDS, PGSS (Precipitation from Gas Saturated Solution)).
These processes have received considerable attention, because they allow homogeneous particles with a diameter smaller than 1 micron to be obtained. In addition these processes allow very good control of size and morphology of powders, the compounds are not subject to mechanical and thermal shock, and the powders obtained are free of any solvent.
Two processes for obtaining micro-particles by supercritical fluids have attained high interest: Rapid Expansion of Supercritical Solutions (RESS) process (Tom, J. W., Debenedetti, P. G. “The formation of bioerodible polymeric microsphere and micro particles by rapid expansion of supercritical solutions” BioTechnol. Prog. 1991, 7, 403–411.) and Gas Anti-Solvent recrystallization (GAS) process (Gallagher, P. M., Coffey, M. P., Krukonis, V. J., Klasutis, N., Am. Chem. Symp. Ser., 1989, No. 406).
In the RESS process the substance of interest is solubilized in a supercritical fluid and the solution is sprayed into a particle formation vessel through a nozzle: rapid expansion of the supercritical solution causes the precipitation of the solute. In some applications it is possible to add a subcritical solvent (modifier) to the supercritical fluid.
A drawback of this technique is that only a few compounds are soluble enough in supercritical fluids, even if a modifier is used. In addition the rapid expansion of supercritical solution through the nozzle can cause the freezing of supercritical fluid and the blockage of the nozzle.
In the GAS process a solute of interest is dissolved in a liquid solvent that is miscible with supercritical fluid, while the solute is not soluble in the supercritical fluid.
The solution is sprayed through a nozzle into a particle formation vessel which is pressurized with supercritical fluid. The rapid and intimate contact between solution and supercritical fluid causes the extraction of solvent from solution in the supercritical fluid and leads to the precipitation of solute as micro-particles. It is possible to enhance the solubility of the liquid solvent in the supercritical fluid by using a modifier. The GAS process overcomes the drawbacks of the RESS process and allows a better control of process parameters.
The crucial step of the GAS process is the mixing of solution and supercritical fluid: in order to obtain an intimate and rapid mixing a dispersion of solution as small droplets into the supercritical fluid is required. Different devices have been proposed to inject solution and supercritical fluid into particle formation vessel in order to obtain a good mixing.
A simple capillary nozzle with a diameter between 0.1 and 0.2 mm has been used first (Dixon D. J. and Johnston K. P., Formation of microporous polymer fibers and oriented fibrils by precipitation with a compressed fluid antisolvent, J. App. Polymer Sci., 50, 1929–1942, 1993).
This device shows high pressure drop along its length leading to a poor conversion of pressure into kinetic energy at the capillary outlet.
Debenedetti P. G., Lim G. B., Prud'Homme R. K. (U.S. Pat. No. 006,063,910, May 16, 2000) use the GAS process to form protein micro particles. In this case the protein solution is sprayed through a laser drilled platinum disc with a diameter of 20 micron and a length of 240 micron inside the particles formation vessel containing the supercritical fluid which is introduced by a different inlet. The laser-drilled platinum disc has an outside diameter of 3 mm, a thickness 0.24 mm, and the orifice is 20 micrometers in diameter. This technique has been used to form particles of catalase and insulin (0.01% w/v) from ethanol/water (9:1 v/v) solutions using carbon dioxide as supercritical fluid. The experiments were carried out at 8.8 MPa and 35° C.; supercritical fluid flow rate was about 36 g/min and the solution flow rate was about 0.35 cc/min.
Compared to a capillary nozzle, the laser drilled disc presents one main advantage: the ratio between length and diameter of the orifice allows minimizing of the pressure drop and energy pressure is almost completely converted into kinetic energy; in such a way, very high solution rates and very small droplets can be obtained.
In this process the supercritical fluid inlet is not optimized: the solution injection occurs in an almost static atmosphere of supercritical fluid, with low turbulence.
Subramaniam B., Saim S., Rajewskj R. A., Stella V. (Methods for particle micronization and nanonization by recrystallization from organic solutions sprayed into a compressed antisolvent. U.S. Pat. No. 5,874,029, Feb. 23, 1999) disclose use of a commercial coaxial convergent-divergent nozzle to inject solution into a particle formation vessel. The nozzle has a convergent-divergent passage for the gas expansion and an inner coaxial capillary tube. The solution injected through the coaxial capillary tube is energized by the expanding gas. The gas that expands in the convergent-divergent nozzle can reach supersonic velocities.
The transition from subsonic to supersonic rate in the nozzle leads to the formation of a Mach disc which enhances dispersion of the solution and mixing between solution and supercritical fluid. Subramaniam et al. propose as energizing gas an inert gas as helium or the supercritical fluid. In the cited examples the authors use the supercritical fluid as the energizing gas.
Even if to reach supersonic velocities very high pressure drops of the energizing gas are required (about 40 MPa), the inventors operate at milder conditions, using pressure drops of about 40 bar (4 MPa), so they could not reach supersonic velocities. Notwithstanding, they claim substantial improvements compared to conventional GAS process.
Experimentally they recrystallised hydrocortisone and camptothecin obtaining powders in the range of nanoparticles (0.5–1 μm).
An advantage of this technique is that the supercritical fluid improves the solution spraying in order to obtain very fine droplets; another advantage is due to the intimate mixing between solution and supercritical fluid which occurs in a very small tract, at the nozzle outlet.
The disadvantage of this technique is that the mixing between solution and supercritical fluid occurs before entering into the particle formation vessel: this situation could lead to particle formation before fluids enter into the particles formation vessel and consequently blockage of the nozzle.
Hanna M., York P. (WO patent application No 96/00610, Jan. 11, 1996) propose a new method and a new apparatus to obtain very small particles by supercritical fluid technique named SEDS (Solution Enhanced Dispersion by Supercritical Solution).
The process is based on a new coaxial nozzle: the solution expands through an inner capillary with a diameter of 0.25 mm; the supercritical fluid expands through an external coaxial pathway with a conically tapering end; the diameter of conical zone at the end is about 0.2 mm. The mixing between the supercritical fluid and the solution occurs in the conical zone. They also propose the use of a three ways nozzle: in the added way a modifier can be fed in order to improve the mixing. They apply the SEDS technology for precipitation of small particles of water soluble compounds, namely sugars (Lactose, Maltose, Trehalose and Sucrose) and proteins (R-TEM beta-lactamase).
The modifier (methanol or ethanol) is introduced into the particles formation vessel either together with the solution or, through a different inlet.
This nozzle allows a good and intimate mixing between the supercritical fluid and the solution: the first contact between supercritical fluid and solution occurs in the conical shaped end, the two fluids emerge from the nozzle outlet at high velocity and the supercritical fluid energizes the liquid solution which breaks into small droplets in the particles formation vessel.
The disadvantage of this technique is related to the contact between supercritical fluid and solution before entering into the particles formation vessel; precipitation of the powder could occur in the nozzle and can eventually cause nozzle blockage.
The supercritical fluid velocity at the nozzle outlet is limited by the orifice diameter that is quite large.
It is known from GM-A-2 322 326 to provide modified apparatus for particle formation using the SEDS technique. The apparatus comprises a particle formation vessel and means for introducing a solution of the substance and a supercritical fluid into said particle formation vessel, said means comprising a nozzle having respective passages for the solution and the supercritical fluid and separate outlets at downstream ends of the respective passages, such that in use contact between the solution and the supercritical fluid first occurs in the particle formation vessel downstream of the separate outlets.